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Nanostructures for modulating intercellular communication and uses thereof

a technology of nanostructures and compositions, applied in the direction of pharmaceutical non-active ingredients, pharmaceutical active ingredients, organic active ingredients, etc., can solve the problems of significant limitations of in vivo applications and variability of methods

Active Publication Date: 2019-09-17
NORTHWESTERN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is about creating nanostructures that can communicate with cells and vesicles to regulate their functions for research, diagnostic, and therapeutic purposes. One aspect of the invention is a synthetic nanostructure vesicle complex, which consists of a vesicle with a surface-bound receptor and a synthetic nanostructure that is attached to the receptor. The nanostructure can contain a diagnostic agent like a tracer lipid or a therapeutic agent like a nucleic acid, antiviral agent, or antineurological agent. The vesicle can be a cell, a virus, an apoptotic body, a synthetic lipid particle, a bacteria, or a fungus. The method for preparing the complex involves contacting a cell or a vesicle with the synthetic nanostructure. The complex can be used for treating vesicle-mediated disorders like cancer, viral infections, neurological disorders, rheumatic diseases, inflammation, antigen presentation, blood disorders, or bacterial infections. The complex can be isolated and detected. Overall, the invention provides a way to regulate intercellular communication and treat diseases by targeting vesicles.

Problems solved by technology

However, these methods have significant limitations for in vivo applications and variability with regard to cargo loading [Johnsen et al.

Method used

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  • Nanostructures for modulating intercellular communication and uses thereof
  • Nanostructures for modulating intercellular communication and uses thereof
  • Nanostructures for modulating intercellular communication and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0267]The present example demonstrates the inhibition of intercellular communication by contacting cells with synthetic nanostructure. As further described below, HDL NPs target SR-B1, manipulate cellular cholesterol homeostasis, and modulate the uptake of exosomes by disrupting lipid rafts.

[0268]HDL NP Synthesis:

[0269]Biomimetic high-density lipoprotein-like nanoparticles (HDL NPs) were synthesized and characterized as previously described [Yang et al. 2013; Luthi et al. 2012; Thaxton et al. 2009]. Briefly, citrate stabilized 5 nm diameter gold nanoparticles (AuNP, Ted Pella) were used as a template for surface chemical modification. Purified human apolipoprotein AI (apoA-I) was incubated with a solution of AuNPs (80 nM) at 5-fold molar excess (400 nM, final) for 1 hour at room temperature (RT) with gentle stirring. Next, the phospholipids, 1-2-dipalmitoyl-sn-glycero-3-phosphocholine and 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-[3-(2-pyridyldithio)propionate] were added a...

example 2

[0305]The present example demonstrates the preparation of synthetic nanostructures with an agent and without an agent and the loading of vesicles with these nanostructures.

[0306]Synthesis of HDL NPs with and without Agents:

[0307]HDL NPs were synthesized using 5 nm citrate stabilized colloidal gold nanoparticles (BBI Solutions) incubated with five-fold molar excess human apolipoprotein AI (Meridian Life Sciences) for one hour with shaking. The phospholipid 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-[3-(2-pyridyldithio)propionate] (DPPTE, Avanti Polar Lipids) was dissolved in ethanol and added in 250-fold molar excess to gold. Other lipids varied depending on the type of particle.

[0308]For particles without tracer, 250-fold molar excess to gold 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC, Avanti) dissolved in ethanol was added and allowed to incubate overnight with shaking.

[0309]For particles with a rhodamine tracer, 200-fold molar excess to gold DPPC dissolved in ethano...

example 3

[0315]The present example demonstrates that identifying and targeting a natural cellular pathway of exosome production provides a new mechanism for efficient and stable manipulation of exosomes that may enable in vivo, ex vivo, or in vitro applications.

[0316]Synthesis of Rh-HDL NPs:

[0317]We synthesized HDL NPs with rhodamine-labeled fluorescent phospholipids (Rh-HDL NP, see below). Data demonstrate that there are ˜17 fluorescent phospholipids on each Rh-HDL NP (Table 1). Also, incorporation of the rhodamine fluorophore was evident by a noticeable absorption peak at 560 nm (FIG. 22). The Rh-HDL NPs have physical properties similar to those of HDL NPs that lack the labeled phospholipid (Table 1).

[0318]

TABLE 1Physical characterization data for Rh-HDL NPs.HDL NPRh-HDL NPSize (nm)13.64 ± 1.2312.85 ± 0.44UV-Vis λmax (nM)519517Zeta Potential (mV)−41.6 ± 0.71−37.9 ± 2.12Rhodamine lipids / particle 0 17

[0319]Characterization of Rh-HDL NP Containing Exosomes:

[0320]We initiated our studies with ...

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Abstract

Nanostructures, compositions and methods for treating vesicle-related or exosome-related conditions are provided. In some cases, the nanostructures and / or compositions may be used to treat cancers, neurological disorders, rheumatologic disorders, viral disorders or other diseases or conditions at least in part by regulating vesicle uptake. Methods of analyzing, imaging and modulating vesicles and cellular vesicles processes are also provided.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]The benefit is claimed of International Application No. PCT / US2015 / 028494, filed 30 Apr. 2015, and U.S. Provisional Application Nos. 62 / 300,349, filed 26 Feb. 2016, 62 / 087,734, filed 4 Dec. 2014, and 61 / 986,360, filed 30 Apr. 2014, the disclosures of which are incorporated by reference in their entireties.STATEMENT OF GOVERNMENT SUPPORT[0002]This invention was made with government support under R01 CA167041 and CA060553 awarded by the National Institutes of Health and FA9550-13-1-0192 awarded by the Air Force Office of Scientific Research (AFOSR). The government has certain rights in the invention.FIELD OF INVENTION[0003]The present invention generally relates to nanostructures and compositions for modulating or monitoring intercellular communication via vesicles and uses thereof.BACKGROUND[0004]One of the major mediators of intercellular communication is exosomes [Martins et al., 2013]. Exosomes are 30-100 nm nanovesicles responsible for...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K31/713A61K47/64A61K47/69
CPCA61K31/713A61K47/6917A61K47/6425
Inventor PLEBANEK, MICHAEL P.THAXTON, C. SHADMUTHARASAN, RAJA KANNANANGELONI, NICHOLAS L.MCMAHON, KAYLIN M.
Owner NORTHWESTERN UNIV
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